{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:21:19Z","timestamp":1760059279715,"version":"build-2065373602"},"reference-count":32,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T00:00:00Z","timestamp":1748908800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation","award":["82330017","82270610"],"award-info":[{"award-number":["82330017","82270610"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Background: Low-dose antibiotic contamination in animal feed is a persistent global food safety challenge. Transient early-life exposure to low-dose penicillin (LDP) is known to induce metabolic syndrome (MetS) in adult mice, but the underlying mechanisms are unclear. Introduction: This study investigated the role of gut microbiota (GM) and intestinal immunity in mediating the long-term metabolic effects of early-life LDP exposure. Methods: Mice were exposed to LDP transiently during early life. GM composition was analyzed. Intestinal IgA responses were quantified. Bacterial encroachment, systemic and adipose tissue inflammation, and diet-induced MetS were assessed. Germ-free (GF) mice received GM transplants from LDP-exposed or control mice to test causality and persistence. Results: Early-life LDP exposure significantly disrupted GM composition, particularly in the ileum, in 30-day-old mice. These GM alterations caused persistent suppression of intestinal IgA responses, evidenced by reduced IgA-producing cells and sIgA levels. This suppression was constrained to early-life exposure: transferring LDP-modified GM to GF mice produced only a transient reduction in fecal sIgA. The LDP-induced sIgA reduction decreased IgA binding of bacteria, leading to increased bacterial encroachment and systemic and adipose tissue inflammation. These pathological changes exacerbated diet-induced MetS. Discussion: Our findings demonstrate that early-life LDP exposure induces persistent intestinal IgA deficiency through lasting GM alterations initiated in early development. This deficiency drives bacterial encroachment, inflammation, and ultimately exacerbates MetS. Conclusions: The exacerbation of diet-induced metabolic syndrome by early-life LDP exposure occurs through an intestinal sIgA-dependent pathway triggered by persistent GM disruption. This highlights a critical mechanism linking early-life antibiotic exposure, gut immune dysfunction, and long-term metabolic health, with significant implications for food safety.<\/jats:p>","DOI":"10.3390\/antibiotics14060574","type":"journal-article","created":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T08:01:07Z","timestamp":1748937667000},"page":"574","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["IgA Dysfunction Induced by Early-Lifetime Low-Dose Antibiotics Exposure Aggravates Diet\u2013Induced Metabolic Syndrome"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2775-4393","authenticated-orcid":false,"given":"Xue","family":"Han","sequence":"first","affiliation":[{"name":"State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China"},{"name":"Beijing Key Laboratory of Viticulture and Enology, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Qin","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Viticulture and Enology, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jielong","family":"Guo","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Viticulture and Enology, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weidong","family":"Huang","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Viticulture and Enology, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yilin","family":"You","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Viticulture and Enology, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8757-7862","authenticated-orcid":false,"given":"Jicheng","family":"Zhan","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Viticulture and Enology, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Yin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/j.cell.2014.05.052","article-title":"Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences","volume":"158","author":"Cox","year":"2014","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/nrendo.2014.210","article-title":"Antibiotics in early life and obesity","volume":"11","author":"Cox","year":"2015","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/nm.4142","article-title":"The microbiome in early life: Implications for health outcomes","volume":"22","author":"Tamburini","year":"2016","journal-title":"Nat. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1038\/nature11400","article-title":"Antibiotics in early life alter the murine colonic microbiome and adiposity","volume":"488","author":"Cho","year":"2012","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"eaao1314","DOI":"10.1126\/sciimmunol.aao1314","article-title":"Microbial antigen encounter during a preweaning interval is critical for tolerance to gut bacteria","volume":"2","author":"Knoop","year":"2017","journal-title":"Sci. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3074","DOI":"10.1073\/pnas.1315792111","article-title":"Secretory antibodies in breast milk promote long-term intestinal homeostasis by regulating the gut microbiota and host gene expression","volume":"111","author":"Rogier","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"28","DOI":"10.4161\/gmic.26489","article-title":"Proteobacteria-specific IgA regulates maturation of the intestinal microbiota","volume":"5","author":"Mirpuri","year":"2014","journal-title":"Gut Microbes"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1542\/peds.2014-3407","article-title":"Antibiotic exposure in infancy and risk of being overweight in the first 24 months of life","volume":"135","author":"Saari","year":"2015","journal-title":"Pediatrics"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1093\/aje\/kwq400","article-title":"Antibiotic exposure by 6 months and asthma and allergy at 6 years: Findings in a cohort of 1,401 US children","volume":"173","author":"Risnes","year":"2011","journal-title":"Am. J. Epidemiol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Sun, Q., Dyar, O.J., Zhao, L., Tomson, G., Nilsson, L.E., Grape, M., Song, Y., Yan, L., and Lundborg, C.S. (2015). Overuse of antibiotics for the common cold\u2013attitudes and behaviors among doctors in rural areas of Shandong Province, China. BMC Pharmacol. Toxicol., 16.","DOI":"10.1186\/s40360-015-0009-x"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1021\/acs.est.6b06424","article-title":"China must reduce its antibiotic use","volume":"51","author":"Ying","year":"2017","journal-title":"Environ. Sci. Technol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Br\u00fcssow, H. (2017). Adjuncts and alternatives in the time of antibiotic resistance and in-feed antibiotic bans. Microb. Biotechnol., 10.","DOI":"10.1111\/1751-7915.12730"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1080\/19440049.2018.1426890","article-title":"Screening of veterinary drug residues in food by LC-MS\/MS. Background and challenges","volume":"35","author":"Delatour","year":"2018","journal-title":"Food Addit. Contam. Part A"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1038\/s41396-019-0349-4","article-title":"The impact of early-life sub-therapeutic antibiotic treatment (STAT) on excessive weight is robust despite transfer of intestinal microbes","volume":"13","author":"Schulfer","year":"2019","journal-title":"ISME J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e37816","DOI":"10.7554\/eLife.37816","article-title":"Antibiotic-induced acceleration of type 1 diabetes alters maturation of innate intestinal immunity","volume":"7","author":"Zhang","year":"2018","journal-title":"Elife"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/s41467-017-00531-6","article-title":"A single early-in-life macrolide course has lasting effects on murine microbial network topology and immunity","volume":"8","author":"Ruiz","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e13155","DOI":"10.1111\/obr.13155","article-title":"Interaction between IgA and gut microbiota and its role in controlling metabolic syndrome","volume":"22","author":"Guo","year":"2021","journal-title":"Obes. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Guo, J.L., Han, X., Zhan, J.C., You, Y.L., and Huang, W.D. (2018). Vanillin Alleviates High Fat Diet-Induced Obesity and Improves the Gut Microbiota Composition. Front. Microbiol., 9.","DOI":"10.3389\/fmicb.2018.02733"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2222","DOI":"10.1126\/science.288.5474.2222","article-title":"A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria","volume":"288","author":"Macpherson","year":"2000","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.chom.2020.01.016","article-title":"Fecal IgA Levels Are Determined by Strain-Level Differences in Bacteroides ovatus and Are Modifiable by Gut Microbiota Manipulation","volume":"27","author":"Yang","year":"2020","journal-title":"Cell Host Microbe"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.4049\/jimmunol.1003181","article-title":"Long-lived plasma cells from human small intestine biopsies secrete immunoglobulins for many weeks in vitro","volume":"187","author":"Mesin","year":"2011","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/nature26138","article-title":"Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance","volume":"555","author":"Ghorpade","year":"2018","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/s41586-020-2564-6","article-title":"Mucosal or systemic microbiota exposures shape the B cell repertoire","volume":"584","author":"Li","year":"2020","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1038\/nri3322","article-title":"New concepts in the generation and functions of IgA","volume":"12","author":"Pabst","year":"2012","journal-title":"Nat. Rev. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1126\/science.1188454","article-title":"Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses","volume":"328","author":"Hapfelmeier","year":"2010","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3650","DOI":"10.1038\/s41467-019-11370-y","article-title":"Gut-associated IgA+ immune cells regulate obesity-related insulin resistance","volume":"10","author":"Luck","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5650","DOI":"10.1038\/s41467-019-13538-y","article-title":"Flagellin-elicited adaptive immunity suppresses flagellated microbiota and vaccinates against chronic inflammatory diseases","volume":"10","author":"Tran","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.chom.2017.10.013","article-title":"Commensal Fungi Recapitulate the Protective Benefits of Intestinal Bacteria","volume":"22","author":"Jiang","year":"2017","journal-title":"Cell Host Microbe"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1126\/science.1221789","article-title":"Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis","volume":"336","author":"Iliev","year":"2012","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/nature14232","article-title":"Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome","volume":"519","author":"Chassaing","year":"2015","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/S0723-2020(99)80053-8","article-title":"The domain-specific probe EUB338 is insufficient for the detection of all Bacteria: Development and evaluation of a more comprehensive probe set","volume":"22","author":"Daims","year":"1999","journal-title":"Syst. Appl. Microbiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1101\/gr.112730.110","article-title":"Chimeric 16S rRNA sequence formation and detection in Sanger and 454-pyrosequenced PCR amplicons","volume":"21","author":"Haas","year":"2011","journal-title":"Genome Res."}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/14\/6\/574\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:46:34Z","timestamp":1760031994000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/14\/6\/574"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,3]]},"references-count":32,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["antibiotics14060574"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics14060574","relation":{},"ISSN":["2079-6382"],"issn-type":[{"type":"electronic","value":"2079-6382"}],"subject":[],"published":{"date-parts":[[2025,6,3]]}}}